Innate immunity constitutes the front line of our defence system against microbes. Antimicrobial peptides (AMPs) are crucial components of innate defences that are synthesized constitutively and/or induced at epithelial surfaces, where the initial contact with microbes takes place (1). AMPs are widespread in nature, from fungi, plants and invertebrates to vertebrates, which establishes these defences are evolutionary conserved. AMPs possess broad activity against various pathogens, i.e. viruses, bacteria, fungi, and parasites (2). There are two major classes of AMPs in mammals, the defensins (α- and β-families) and the cathelicidins (3, 4). Besides the microbicidal activity (5), these peptides have been shown to act as chemo-attractants for cells of both the adaptive and innate immunity and to modulate immune responses (6-8). Thus, AMPs constitute a link between the innate and adaptive immunity.
The expression of AMPs can be induced by certain compounds. Butyrate (BA) was found to induce cathelicidin expression in epithelial cells (9). Moreover, sodium butyrate counteracted pathogen down-regulation of AMPs expression, resulting in pathogen elimination from epithelial surfaces in vivo in a rabbit model of Shigellosis (10). Phenylbutyrate (PBA), an analogue of butyrate, was shown to upregulate the expression of LL-37, the sole cathelicidin in humans, in epithelial cell lines and in monocytes (11). The active form of Vitamin D3, 1,25-dihydroxyvitamin D3, was also reported to enhance the expression of LL-37 in keratinocytes, immune cells, and in epithelial cells (12-14). Interestingly, PBA and 1,25-dihydroxyvitamin D3 were found to up-regulate LL-37 in a synergistic manner (11).
The continual emergence of antibiotic resistance among bacterial pathogens poses a great challenge to the public health. The pipeline of new antibiotics in drug development has yet to match this threat, since only few novel agents have been developed in the last decades (15, 16). Strengthening immune defences against pathogens by boosting the expression of our own “natural antibiotics” may represent novel or complementary pharmaceutical interventions in infectious diseases. Importantly, the multiplicity of AMPs with overlapping antibacterial mechanisms secures minimal risk of microbial resistance (17).
WO2009/087474 (Akthelia Pharmaceuticals) concerns generally the use of phenylbutyrate and similar compounds and their glycerol esters, and other compounds including vitamin D, for treating, preventing or counteracting microbial infections in animals by stimulating the innate antimicrobial peptide defence system, such as LL-37 in humans. Preferred compounds include phenyl substituted butyrate derivatives. This publication describes, inter alia, how CAP-18 (the rabbit homologue to LL-37) is induced in the rabbit colonic epithelium following oral administration. The publication further describes the expression of LL-37 in a bronchial epithelial cell line VA10. The publication further describes the cure of rabbits from shigellosis.
WO2012/0140504 (Raqib et al) also relates to the use of compounds for stimulating the innate antimicrobial peptide defence system, such as LL-37 in humans, in particular novel targets, organs, cells or tissues.
WO2008/073174 (GALLO) describes methods and compositions for modulating gene expression and the innate immune response by use of 1,25(OH)2 vitamin D3 (1,25D3). That compound is tested alongside non-specific histone deacetylase inhibitors (HDACi) including butyrate or trichostatin A.
US20080038374 (Stahle) describes use of a vitamin D compound, which is able to specifically and directly up-regulate hCAP18, for the manufacturing of a medicament with antimicrobial effect for treatment of conditions deficient in LL-37, such as chronical ulcers, and atopic dermatitis.
Liu et al “Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response” 24 Mar. 2006 VOL 311 SCIENCE, pp 1770-1773, describes data which is said to support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection, such as Mycobacterium tuberculosis. 
Hata et al. (2008) “Administration of oral vitamin D induces cathelicidin production in atopic individuals” J ALLERGY CLIN IMMUNOL, VOLUME 122, NUMBER 4, described a study in which 14 normal controls and 14 atopic subjects with moderate to severe atopic dermatitis were treated with oral vitamin D3 to see if this could overcome the relative deficiency in induction of cathelicidin in the atopic patients. After supplementation with 4000 IU/d oral vitamin D for 21 days, AD lesional skin showed a statistically significant increase in cathelicidin expression.
The synergistic effects of PBA and vitamin D has been demonstrated in vitro in the VA10 cell line in a publication by Steinmann et al (2009) ANTIMICROBIAL AGENTS AND CHEMOTHERAPY (53), 5127-5133.
Martineau et al (Lancet 2011; 377: 242-50) describes a Phase II study of TB patients treated with high dose vitamin D.
US 200210076393 A1 relates to a method for the stimulation of defensin production in eukaryotic cells such as, for example, mammalian cells and various organs, using isoleucine or active isomers or analogs thereof. It further relates to methods for the prevention and treatment of infections and other various disease states and in the stimulation of the immune system in various tissues in which defensins are found.
Despite the above disclosures, it will be appreciated that the provision of compounds or combinations of compounds for use in enhancing the innate immune response against organisms or diseases not previously identified targeted in this way, or in tissues over and above those previously identified, would provide a contribution to the art.